1. Field of the Invention
The present invention relates to a novel method of producing dulofibrate, a product useful in the treatment of hyperlipermias.
2. Discussion of the Background
Dulofibrate is the p-chlorophenol ester of p-chlorophenoxyisobutyric acid. Its therapeutic use is described in French Pat. No. 77-06689, filed Mar. 8, 1977.
A number of methods of preparing esters of p-chlorophenoxyisobutyric acid (clofibric acid) are known. The alcohol esters of clofibric acid can be prepared from clofibric acid and the corresponding alcohol in the presence of H.sup.+ ions, but this method is not applicable to phenol esters, and thus cannot be considered for manufacturing dulofibrate.
Another, more general method of preparing esters of clofibric acid consists of reacting a derivative of clofibric acid such as an acyl chloride or an acid anhydride, with a hydroxy-compound in the presence of, e.g., an organic tertiary amine, in a non-polar solvent such as toluene or benzene. This method can be employed for preparation of dulofibrate, and has been described in French Pat. No. 77-06689. A variant consists of reacting the clofibric acid and the hydroxy-compound which is to be esterified, in the presence of dicyclohexylcarbodiimide.
The clofibric acid is prepared generally from p-chlorophenol and acetone in the presence of sodium hydroxide and chloroform use (see Kleeman, A., and Engel, J., 1982, "Pharmaceutical substances--syntheses, patents, and applications" (in German, as "Pharmazeutische Wirkstoffe. Synthese. Patente. Anwendungen."), Vol. II., publ. Georg Thieme Verlag, New York).
Known methods for the preparation of clofibrate esters are lengthy and require numerous steps. Accordingly, in view of the usefulness of clofibrate esters, there is a strongly felt need for their ready preparation.